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CONCISE REPORT Renal in the antiphospholipid (Hughes) syndrome and S R Sangle, D P D’Cruz, W Jan, M Y Karim, M A Khamashta, I C Abbs,GRVHughes ......

Ann Rheum Dis 2003;62:999–1002

11 with primary APS, and 6 with aPL only) and uncontrolled Background: Hypertension is common in the anti- hypertension. All patients had attended the St Thomas’ phospholipid (Hughes) syndrome (APS) and its cause is Hospital Lupus Unit over the previous five years. Patients with poorly understood. Anecdotal evidence suggests that renal SLE were classified by the American College of Rheumatology artery stenosis (RAS) may be a relevant and treatable classification criteria for SLE.7 Patients with APS had a history cause of hypertension. of or pregnancy morbidity, or both, in addition to Objective: To investigate the prevalence of RAS in positive aPL on two separate occasions at least six weeks apart, patients with APS and hypertension. as defined by the preliminary classification criteria established Patients and methods: Three groups of patients were in Sapporo.8 Six patients had only positive aPL antibodies. evaluated: (1) 77 patients with positive antiphospholipid Group 2: 91 hypertensive patients attended the hypertension antibodies (aPL) (60 secondary APS, 11 primary APS, and and renal clinics in St Thomas’ and Guy’s Hospital and were 6 with aPL only) and uncontrolled hypertension who were investigated for their uncontrolled hypertension. receiving two or more antihypertensive drugs; (2) 91 patients (<50 years) attending hypertension clinics;(3) 92 Group 3: 92 healthy, normotensive, aPL antibody negative normotensive healthy, potential renal transplant donors. patients, who were assessed before considering donation of a Magnetic resonance renal angiography was used to kidney for transplantation. image the renal in all three groups. Patients in group 1 were assessed prospectively and groups Results: Group 1: 20/77 (26%) patients had evidence of 2 and 3 were assessed in the previous three years. RAS (16 unilateral and 4 bilateral). Sixteen patients (80%) was measured at every clinic visit (three had smooth well defined stenoses in the proximal third of months) in groups 1 and 2. All patients with APS had had the renal artery. Three further patients had irregular arter- repeated blood pressure measurements >150/100 mm Hg ies without distinct stenosis. Group 2: 7/91 (8%) hyperten- despite receiving two or more antihypertensive agents. sive patients had RAS (χ2=10.3, p<0.001 v group 1). Magnetic resonance imaging angiography (MRA) was used Group 3: 3/92 (3%) healthy donors had RAS (χ2=18.2, non-invasively to image the renal arteries in the St Thomas’ p<0.0001 v group 1). Hospital radiology department. A bolus of contrast medium Conclusion: A significantly increased prevalence of RAS gadolinium 0.3 ml/kg body weight was injected into the (26%) was found in patients with APS and hypertension, antecubital . The image acquisition was performed after compared with relatively young (<50 years) hypertensive visualisation of the aorta and its renal branches using the controls and healthy potential donors. bolus track. T1 and T2 weighted images were processed with maximum intensity projection construction by an experienced radiologist at a workstation. MRA (73 patients) was used to study the renal arteries, two patients had contrast computed n 1934 Goldblatt and Lynch demonstrated that hyper- tomography (CT) angiography, and two underwent intra- tension could be produced in dogs by constricting both renal venous contrast angiography, as MRA was not possible. In Iarteries or removal of one kidney.1 In 1938 Houssay and groups 2 and 3, all patients had MRA of the renal arteries Taqueni provided evidence for the role of renin in the develop- using the same protocol. ment of hypertension in the ischaemic kidney.2 Since then extensive clinical experience has linked Baseline clinical parameters (RAS) or occlusion with hypertension. Recently a “new” and Group 1 comprised 65 women and 12 men with a median age possibly major cause of renovascular hypertension—the anti- of 45 years (range 19–72). The racial distribution included 61 phospholipid syndrome (APS, Hughes syndrome), has been white, 9 black, and 7 patients of Asian origin. The median added to the list.3–6 Hypertension was noted in the original duration of disease was 16 years (range 4–23). The median µ descriptions of APS, and was thought to be secondary to reno- creatinine concentration was 184 mol/l. Eleven patients were vascular changes.3 We considered that renal artery occlusion, diabetic and 10 hyperlipidaemic, for which they were receiving as in other arteries, might be a feature of APS.3 In 2000 we lipid lowering agents. The mean systolic blood pressure of all published an account of a small series of patients with RAS in the patients was 160 mm Hg and diastolic 100 mm Hg. Three patients with APS associated with hypertension.6 We consid- patients were overweight (body mass index (BMI) >28) and ered it important, therefore, to establish the prevalence of RAS 11 were chronic smokers (table 1) These results refer to the in a group of patients with APS with uncontrolled hyper- whole of group 1 not just the patients with RAS. tension. Ethical approval was obtained for this preliminary study from the St Thomas’ Hospital ethics committee...... PATIENTS AND METHODS Abbreviations: aCL, anticardiolipin antibodies; aPL, antiphospholipid We evaluated three groups: antibodies; APS, antiphospholipid syndrome; BMI, body mass index; CT, computed tomography; INR, international normalised ratio; MRA, Group 1: 77 patients with positive antiphospholipid antibodies magnetic resonance imaging angiography; ox-LDL, oxidised low density (aPL) (60 with systemic lupus erythematosus (SLE) and APS, lipoprotein; RAS, renal artery stenosis; SLE, systemic lupus erythematosus

www.annrheumdis.com 1000 Sangle, D’Cruz, Jan, et al

Table 1 Baseline parameters of patients with APS and hypertension

Patients with no Patients with Patients (n=77) RAS (n=57) RAS (n=20)

Primary APS 9 4 Secondary APS 48 16 Median age (years) 45 43 Mean systolic BP (mm Hg) 160 155 Mean diastolic BP (mm Hg) 100 104 Median creatinine (µmol/l) 184 185 Diabetes 11 2 Smoking 10 1 Steroids (prednisolone) 26 10 Hyperlipidaemia 10 2 Obesity/overweight 2 1 Nephritic/ 11 2 Past thrombotic events 55 18 (arterial/venous) Pregnancy related morbidity 41 4 Figure 1 Magnetic resonance angiography showing renal artery APS, antiphospholipid syndrome; RAS, renal artery stenosis. stenosis in a patient with APS and hypertension.

All except 12 patients had had other arterial/venous throm- botic episodes such as cerebrovascular accident, deep , pulmonary , ischaemic heart disease, and gangrene. Forty two patients had pregnancy related com- plications. Six patients were positive for aPL only, without any vascular occlusions or pregnancy related morbidity. In group 2, 91 hypertensive (≤50 years) patients were investigated for their uncontrolled hypertension. Their mean age was 42 years (18–50) and 46 were female. Group 3 consisted of 92 healthy subjects, who were investigated as prospective kidney donors. Their mean age was 52 years (22– 59). Statistical analysis Categorical data were assessed non-parametrically with the χ2 test with Yates’s correction for small numbers where appropriate.

RESULTS Imaging of renal arteries Figure 2 RAS confirmed on arteriography. The lesion is a long Examination of the renal arteries in group 1 (77 patients) smooth stenosis with no evidence of . showed RAS in 20 patients (26%). In 16 the lesions were uni- lateral, while four had bilateral RAS. Sixteen patients had respectively. Two were diabetic and two had hypercholesterol- smooth well delineated stenoses situated in the proximal one aemia. Their median age was 43 years (19 –62). One patient third of the artery from the ostium (figs 1 and 2). In these 16 had had of the descending aorta. One of these patients, the aorta above and below the renal arteries was patients was obese and all were Caucasian in origin. Eighteen uniformly smooth and regular. The remaining four had of these patients had had venous or arterial thrombotic events. irregular, tortuous renal arteries and aorta, suggesting athero- Four patients had pregnancy related morbidity. sclerotic lesions. Three further patients had irregular renal arteries, without evidence of distinct stenosis. Fifteen of the 20 Therapy patients had secondary APS and three had primary APS. Two All but two patients with RAS were treated with anticoagu- patients with RAS were aPL positive only. In group 2 of young lants (recommended international normalised ratio (INR) hypertensive patients, 7/91 (8%) patients had RAS and in five 3.0–4.0). the appearance was suggestive of fibromuscular dysplasia. In The indication for anticoagulation in 14 patients was recur- group 3, only 3/92 (3%) subjects had RAS. The prevalence of rent arterial/or venous thrombosis. Four patients were anti- RAS was significantly higher in group 1 than in both control coagulated as it was thought that RAS as a potential groups (χ2=10.3, p=0.001 v group 2 and χ2 =18.2, p<0.0001 v thrombotic event might compromise renal function. group 3). Patients with APS with RAS Progress of patients Renal parameters MRA/CT contrast angiography was repeated in five patients In the patients with APS, the median creatinine level was 185 for suspected re-stenosis (renal bruit 3, impaired renal µmol/l (range 64–350). Two patients had had significant pro- function 3, uncontrolled blood pressure 2). All five had previ- teinuria (>3.0 g/day) and microangiopathic lesions on renal ously undergone angioplasty of stenosed renal arteries and biopsy. None of the patients had fragmented red blood cells or stents were inserted in three. All these patients were granular casts on urine analysis. anticoagulated after angioplasty. On re-imaging two of the five showed evidence of renal Other parameters arterial re-stenosis. Interestingly, one patient who was not The mean systolic and diastolic blood pressure of these anticoagulated and the other, who was inadequately anti- patients with RAS was 155 mm Hg and 104 mm Hg, coagulated (mean INR <2.3), were the two patients who

www.annrheumdis.com Renal artery stenosis in the APS syndrome 1001 re-stenosed. The remaining three patients whose INR was ,17 and that aPL are the biggest single risk maintained at >3.0 showed no evidence of re-stenosis. All factor.18 At a molecular level, anticardiolipin antibodies (aCL) other patients with RAS and a mean INR maintained at >3.0 have been shown to have atherogenic properties. For example, showed good control of blood pressure and stable renal aCL can cross react with oxidised low density lipoprotein (ox- parameters, suggesting that adequate anticoagulation may be LDL), and may enhance the in vitro uptake of ox-LDL by important in maintaining the patency of the renal arteries. monocytes.19 20 Ox-LDL is considered to be a major antigen in the development of the atherosclerotic plaque, and its DISCUSSION enhanced uptake into monocytes/macrophages may be play a The most common primary renal diseases of the renal arteries part in the progression from to plaque. There is are atherosclerotic RAS and fibromuscular dysplasia. These also a possibility that a third factor, “endothelin” has a role in lesions are associated with two common syndromes—namely, vasoconstriction in these patients. Atsumi et al described hypertension and ischaemic nephropathy. Fibromuscular dys- increased endothelin levels in patients with APS and arterial 21 plasia accounts for 10% of these stenoses, the rest being occlusions. Endothelial cell activation, which may occur in 18 atherosclerotic. The prevalence of RAS in atherosclerotic early atherosclerosis, may be induced in vitro by aCL. patients increases with age, particularly in patients with Intra-arterial radiocontrast angiography is the traditional diabetes, peripheral arterial occlusive disease, atherosclerosis, method for assessing renovascular disease. However, non- and coronary artery disease.9 The existing data on the invasive assessment is now reliable and safe. Gadolinium enhanced MRA has been shown to be a sensitive (84%) and prevalence of renovascular hypertension are based on 9 necropsy findings and angiography carried out owing to reno- specific (91%) technique producing excellent images. Fur- vascular hypertension. Renovascular hypertension accounts ther, gadolinium is non-nephrotoxic and can be used in for about 5% of the American hypertensive population.2 chronic renal failure—for example, secondary to lupus nephritis. There are, of course, restrictions to MRA—for Several studies have shown a correlation between increasing example, in the presence of marked obesity, pacemaker age and the presence of renal artery atherosclerosis.210Bacha implantation, intracranial metallic clips, claustrophobia, etc. et al described an increased prevalence of renovascular disease In addition, in a few cases that we have observed, MRA (20%) in patients with diabetes and hypertension.11 12 The suggested suspicious lesions, but angiography was required mean age of these patients was >61 years.11 Similarly Jean et for a definitive diagnosis. In particular, distal segments and al found a high prevalence of RAS in elderly patients (mean 13 small accessory arteries are less reliably visualised with age >63 years) with coronary heart disease. RAS was also an MRA.22 MRA has been shown to overestimate the prevalence independent feature in patients with peripheral vascular dis- of stenotic lesions by 15%.23 However, the use of two control ease, and its prevalence increased with the severity of the per- 14 groups using the same protocol minimises this effect in our ipheral . The mean age of these patients was study. 73 years. Our findings also have therapeutic implications. The finding We have demonstrated a significantly higher prevalence of of RAS either by MRA or angiography necessitates a clinical RAS (26%) in patients with APS who have difficult to control decision about treatment. Our preliminary data, especially in hypertension than in a hypertensive group and otherwise the patients who developed re-stenosis of their renal arteries, healthy potential renal donors. Ideally, a group of patients suggest that anticoagulation may be a potential treatment. with SLE without APS should be compared with the patients Furthermore, Remondino et al reported that anticoagulation with SLE and APS. However, ethical and economic reasons with acenocumarol was successful in recanalising bilateral made this difficult. Nevertheless, we managed to compare our RAS in a patient with secondary APS.24 Thus anticoagulation ≤ results with relatively young hypertensive ( 50 years) patients should be carefully considered to stabilise or improve the ste- without APS and another control group of normotensive, nosis, to prevent re-stenosis after angioplasty, and as prophy- healthy potential kidney donors. laxis against thrombosis elsewhere. This study suggests that RAS may be an important cause of Local treatment of the stenosis may involve percutaneous hypertension in APS. In 1991 we reported a single patient with transluminal balloon angioplasty with or without stenting or 5 hypertension, RAS, and primary APS, and in 2000 followed surgery.9 Aizawa et al reported a patient with APS associated with a series of five patients with APS and hypertension who RAS treated successfully with angioplasty.25 However, factors 6 had RAS. This study considerably extends and confirms these needing to be considered include (a) the nature of the findings. stenosis—long and irregularly stenosed arteries suggestive of The type of stenotic lesions observed in 16 patients with atherosclerosis are less amenable to angioplasty; (b) the APS is rather unusual. Most were in the proximal segment of patient’s underlying renal function—patients who have the renal arteries and they are smooth and well delineated chronic renal impairment are at risk of further deterioration of (figs 1 and 2). These lesions appear to be quite different from their renal function if they develop radiocontrast nephropa- those seen in the stenoses of atherosclerosis and fibromuscu- thy; (c) the severity of hypertension—if the blood pressure is lar dysplasia and potentially constitute a lesion that is unique well controlled, albeit with two agents, then an invasive to this syndrome. Our findings extend to patients with both procedure may not be justified. primary and secondary APS. Indeed, two patients with RAS The alternative to angioplasty is, of course, surgical and uncontrolled blood pressure only had aPL without previ- intervention, which is reserved for severe lesions not amena- ous thrombosis and morbidity. This has diagnostic and thera- ble to angioplasty. Anticoagulation is still essential even if peutic implications. Thus when any aPL positive patient local treatment is undertaken in order to prevent re-stenosis develops hypertension, the doctor should look beyond the tra- and extrarenal thrombosis. In this series we report the ditional risk factors such as corticosteroid treatment and successful combination of renal artery angioplasty and underlying lupus nephritis and consider investigation for anticoagulation in three patients. renovascular disease. Other risk factors for atherosclerosis are important, and The high prevalence of RAS in our patients with APS clearly the hypertension resulting from RAS may itself suggests that there might be a pathophysiological relation- exacerbate the process. RAS is common in patients with ship. APS is by definition a prothrombotic state, and both diabetes, coronary artery disease, peripheral vascular disease, arterial and venous thromboses are typical features. Thrombo- and atherosclerosis.10–14 Its prevalence increases with age sis in the renal arteries and has been reported.15 16 (mean age >60 years)210 and duration of diabetes.12 Our Beyond this propensity to thrombosis there is also mounting patients were much younger than these previously reported evidence that patients with APS may develop accelerated series with a median age of 43 years (19–62). Only two of the

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20 patients had relatively recent onset diabetes (4 and 6 2 Venkatesan J, Henrich W. Ischaemic renal disease. In: Seldin D, ed. years). Only one was overweight (BMI >28) and two had The kidney. 3rd ed. Vol 2. Philadelphia: Lippincott Williams and Wilkins, 2000:2437–56. hyperlipidaemia (table 1). Ten patients (all secondary APS) 3 Hughes G. Connective tissue diseases and the skin. The 1983 were receiving long term steroids and two (primary APS) had Prosser-White Oration. Clin Exp Dermatol 1984;9:535–44. 4 Hughes GRV. Off the beaten track: a clinician’s view. In: Khamashta nephrotic syndrome, which might have been secondary to MA, ed. Hughes syndrome (antiphospholipid syndrome). London: microthrombi in the glomerular capillaries. Clinically there Springer, 2000:105–10. was no evidence of peripheral vascular occlusion in any 5 Asherson RA, Noble GE, Hughes GR. Hypertension, renal artery stenosis and the “primary” antiphospholipid syndrome. J Rheumatol patient. It is unlikely, therefore, that traditional atheromatous 1991;18:1413–15. risk factors, other than corticosteroids, have a major role in the 6 Godfrey T, Khamashta MA, Hughes GRV. Antiphospholipid syndrome development of RAS in these patients. Our findings suggest and renal artery stenosis. QJM 2000;93:127–9. 7 Hochberg MC. Updating the American College of Rheumatology revised that a prothrombotic tendency probably has a major role in criteria for the classification of systemic lupus erythematosus. Arthritis the development of RAS in patients with APS. The role of Rheum 1997;40:1725. accelerated atheroma needs further evaluation. 8 Wilson WA Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification Although we have clearly defined renal arterial disease as criteria for definite antiphospholipid syndrome: report of an international occurring in patients with APS, it is important to note that workshop. Arthritis Rheum 1999;42:1309–11. renal microvascular disease is also a recognised feature of 9 Safian RD, Textor SC. Renal-artery stenosis. N Engl J Med 26 2001;344:431–42. APS. The pathological hallmark in the kidney is thrombotic 10 Scoble JE, de Takats D, Ostermann ME, Connolly JO, Scott NR, Beeso . Renal microvascular disease in APS can JA, et al. Lipid profiles in patients with atherosclerotic renal artery present in a variety of ways, including haematuria, proteinu- stenosis. Nephron 1999;83:117–21. 11 Bacha J, Aboud E, Correges JP. Prevalence and aspects of arteriopathies ria, renal impairment, or hypertension. In fact, the most com- in non-insulin dependent diabetes mellitus with severe hypertension. Arch mon clinical correlate of renal microvascular disease is hyper- Mal Coeur Vaiss 1997;90:1065–9. tension as reported in 15/16 patients in the series of Nochy et 12 Courreges JP, Bacha J, Aboud E, Andre L, Lamacra R. Renal artery 27 stenosis and chronic renal failure in NIDDM. Arch Mal Coeur Vaiss al. Thus, although we would suggest that the finding of 1998;91:1077–82. hypertension in a patient with APS should certainly lead to an 13 Jean WJ, al-Bitar I, Zwicke DL, Port SC, Schmidt DH, Bajwa TK. High investigation of the renal arteries, there may also be a case for incidence of renal artery stenosis in patients with coronary artery disease. Cathet Cardiovasc Diagn 1994;32:8–10. considering renal microvascular disease, particularly in the 14 Missouris CG, Buckenham T, Coppuccio FC,MacGregor GA. Renal presence of other signs of intrinsic renal disease. artery stenosis: a common and important problem with peripheral In summary, we report a significantly higher prevalence of vascular disease. Am J Med 1994;96:10–14. 15 Rysava R Zabka J, Peregrin JH,Tesar V, Merta M, Rychlik I. Acute renal RAS in patients with APS and hypertension compared with failure due to bilateral renal artery thrombosis associated with primary two control groups. These lesions appear to be quite different antiphospholipid syndrome. Nephrol Dial Transplant 1998;13:2645–7. 16 Morgan RJ, Feneley RC. Renal vein thrombosis caused by primary from those seen in atherosclerotic RAS or fibromuscular dys- antiphospholipid syndrome. Br J Urol 1994;74:807–8. plasia and may be unique to this syndrome. Possibly, APS will 17 George J, Shoenfeld Y. The antiphospholipid “Hughes syndrome”: a prove to be an important cause of RAS in the younger age cross roads of autoimmunity and atherosclerosis. Lupus 1997;6:559–60. 18 Harats D, George J, Levy Y, Khamashta MA, Hughes GR, Shoenfeld Y. groups. Atheroma: links with antiphospholipid antibodies, Hughes syndrome and lupus. QJM 1999;92:57–9. ACKNOWLEDGEMENTS 19 Vaarala O, Alfthan G, Jauhiainen M, Leirisalo-Repo M, Aho KND, Palosuo T. Crossreaction between antibodies to oxidized low-density Lupus UK, the St Thomas’ Lupus Trust, The Arthritis Research Cam- lipoprotein and to cardiolipin in systemic lupus erythematosus. Lancet paign; Dr John Scoble, director and consultant in renal medicine, 1993;ii:923–5. Guy’s and St Thomas’ Hospital NHS Trust, London; Professor J M Rit- 20 Hasunuma Y, Matsura E, Makita Z, Katahira T, Nishi S, Koike T. ter, Hypertension Clinic, Guy’s and St Thomas’ Hospital NHS Trust, Involvement of β2 glycoprotein I and anticardiolipin antibodies in London. oxidatively modified low density lipoprotein uptake by macrophages. Clin Exp Immunol 1997;107:569–74. 21 Atsumi T, Khamashta MA, Haworth RS, Brooks G, Amengual O, ...... Ichikawa K, et al. Arterial disease and thrombosis in the antiphospholipid Authors’ affiliations syndrome, a pathogenic role for endothelin 1. Arthritis Rheum 1998;41:800–7. S R Sangle, D P D’Cruz, M Y Karim, M A Khamashta, 22 Gedroyc WM, Neerhut P, Negus R, Palmer A, al Kutoubi A, Taube D, et G R V Hughes, The Lupus Research Unit, The Rayne Institute, al. Magnetic resonance angiography of renal artery stenosis. Clin Radiol Lambeth Wing, St Thomas’ Hospital, London SE1 7EH, UK 1995;50:436–9. W Jan, Radiology Department, Guy’s and St Thomas’ Hospital, London 23 Marcos HB, Choyke PL. Magnetic resonance angiography of the kidney. SE1 7EH, UK Semin Nephrol 2000;20:450–5. I C Abbs, Renal Unit, Guy’s and St Thomas’ Hospital, London SE1 7EH, 24 Remondino GI, Mysler E, Pissano MN, Furattini MC, Basta MC, Presas UK JL, et al. A reversible bilateral renal artery stenosis in association with antiphospholipid syndrome. Lupus 2000;9:65–7. Correspondence to: Dr S R Sangle; [email protected] 25 Aizawa K, Nakamura T, Sumino H, Saito Y, Hoshino J, Kurashina T, et al. Reno-vascular hypertension observed in a patient with Accepted 17 February 2003 antiphospholipid-antibody syndrome. Jpn Circ J 2000;64:541–3. 26 Amigo MC, Garcia-Torres R, Robles M, Bochicchio T, Reyes PA. Renal involvement in primary antiphospholipid syndrome. 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